1. PROJECT SUMMARY/ABSTRACT Omniox is developing a unique oxygen delivery protein, OMX, as a treatment to preserve myocardial and peripheral organ function and significantly reduce morbidity after neonatal cardiopulmonary bypass (CPB) during surgical correction of congenital heart disease (CHD). Of the ~40,000 children born annually with CHD, ~10,000 require urgent surgery to repair heart defects. Up to 60% of infants who undergo CPB will experience post-operative complications that can result in peripheral organ dysfunction and long-term neurological deficits. A critical driver of the myocardial and peripheral organ tissue damage is oxygen deprivation, or hypoxia. However, there are no current or promising therapeutic approaches that target hypoxia during CPB surgery to stem or alleviate its damaging downstream effects. Omniox' lead therapeutic candidate, OMX, is designed to restore physiologic oxygen levels in hypoxic tissues. Thus, OMX has the potential to address a high unmet need of preserving myocardial function and improving morbidity associated with neonatal CPB surgery. Together with our collaborators, neonatal and pediatric care intensivists Drs. Fineman and Maltepe at the University of California, San Francisco (UCSF), we have demonstrated that OMX attenuates hypoxia- induced myocardial dysfunction in lambs. Furthermore, our preliminary data demonstrate that OMX: 1) restores physiologic oxygen levels specifically in oxygen-deprived tissues; 2) prevents hypoxia-induced cell death after brain ischemia; 3) is stable, safe, and well tolerated in multiple species; and 4) does not increase free radical production or scavenge nitric oxide. The objective of this Fast-Track SBIR Phase I/II proposal is to complete preclinical development of OMX as a novel biologic for the treatment of neonates undergoing CPB by demonstrating its therapeutic utility in oxygenating hypoxic tissue and preserving myocardial and peripheral organ function. We propose to 1) demonstrate OMX preserves myocardial and peripheral organ function during and after CPB in intact newborn lambs (Phase I), then 2) demonstrate OMX' efficacy in a clinically relevant neonatal lamb CHD model undergoing CPB (Phase II). These data will inform an IND application for a neonatal and pediatric clinical trial. Pending good safety and efficacy data in neonatal and pediatric patients undergoing CPB, Omniox plans to expand OMX use to other pediatric indications in which hypoxia drives disease pathology such as persistent pulmonary hypertension in neonates and birth asphyxia.